The aim of the project is to investigate genetic alterations underlying tumor development and progression. Emphasis is placed on the study of human cancer as it occurs in vivo, and the integration of basic research, clinical information, and developing technologies. The four areas of focus are, a) Technology/methodology development, b) Prostate cancer, c) Multiple Endocrine Neoplasia Type I (MEN1), and Esophageal Squamous Cell Cancer (ESCC). To overcome the problems of tissue heterogeneity we participated in the development of laser capture microdissection (LCM) and layered expression scanning, techniques which are useful in molecular profiling studies. In parallel, several associated methodologies have been developed to improve the accuracy and sensitivity of molecular analysis of clinical tissue specimens. The laboratory is taking a 3-dimensional analytical approach to study prostate cancer which allows the entire prostate gland to be studied and the physical and molecular relationship of tumor progression to be determined. An important future goal is to integrate genomic and protein data with gene expression datasets such that a comprehensive analysis of the status of genes and gene products will be possible. MEN1 is an inherited syndrome characterized by development of multiple neuroendocrine (NE) tumors in affected individuals. The responsible gene was recently discovered by the NIH MEN1 working group, including the Pathogenetics Unit and groups from NHGRI, NCBI, and NIDDK. Germline mutations in the MEN1 gene result in formation of NE tumors in a predictable manner and include tumors from multiple organs. Thus, studies of the gene and gene product (menin) are a unique and exciting opportunity to gain new insights into fundamental events and principles of tumor formation. The PG Unit is collaborating with the Cancer Prevention Studies Branch, CCR, NCI to examine the genomic alterations that occur in esophageal cancers from a high-risk population in Shanxi Province, China. Results to date have identified several regions of the genome that are likely to harbor tumor suppressor genes, and also point to the presence of an inherited tumor susceptibility gene located on chromosome 13.